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Emicizumab is a bispecific antibody that mimics the function of factor VIII (FVIII) and is indicated for prophylactic use in patients with congenital hemophilia A with or without inhibitors. Acquired hemophilia A (AHA) is a rare and severe disorder causes by autoantibodies that inhibit FVIII. In AHA, acute bleeding are managed with bypassing agents but several reports described the off-label use of emicizumab. The aim of this article is to describe two cases of AHA treated with emicizumab and a review of the scientific littérature. Reports indicate that the use of emicizumab is efficacious to treat acute bleeding with less thrombotic events thant with bypassing agents and with a reduced hospitalisation duration. Nevertheless biological monitoring is more complicated with assay interferences and a persistent circulation more than 6 months after the last injection was observed for our two patients.
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BACKGROUND: Preoperative identification of patients with haemostasis abnormalities leading to an increased bleeding risk was based on routine haemostasis tests: prothrombin time (PT), activated prothrombin time (aPTT), and platelet count. Because of their low predictive performance, guidelines recommend replacing them with structured bleeding risk questionnaires, but none is validated in this population. OBJECTIVES: To assess the diagnostic accuracy of 3 strategies, performed at the pre-anaesthesia visit before scheduled interventions, to identify patients with haemostasis abnormalities leading to an increased bleeding risk PATIENTS AND METHODS: Multicenter study in 7 French academic hospitals, involving patients scheduled for surgical intervention, without antiplatelet/anticoagulant treatment. The 3 strategies consisted of 1-a structured screening questionnaire; 2-PT, aPTT, and platelet count ordered in selected patients; 3-systematic PT, aPTT, and platelet count. The reference standard comprised von Willebrand factor activity/antigen, factors VIII, IX, and XI, platelet-function analyser, and, when required, FII, FV, FX, and FVII and haemostasis consultation. RESULTS: Eighteen (1.2%) of 1484 patients had a haemostasis abnormality leading to an increased bleeding risk according to reference standard. In the overall cohort, sensitivity of the questionnaire-based strategy was 50% (95%CI, 26-74; specificity 87% (95%CI, 85-88); sensitivity was 0 (95%CI, 0-41) in men vs 82% (95%CI, 48- 98) in women. For selective routine tests, sensitivity was 33% (95%CI, 13-59) and specificity 97% (95% CI, 96-98). Corresponding values for systematic routine tests were 44% (95%CI, 22-69) and 93% (95%CI, 91-94). CONCLUSIONS: Sensitivity was low for all 3 strategies investigated. The structured screening questionnaire had clinically acceptable diagnostic accuracy only in women.
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Background: Despite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. Objectives: This multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. Methods: One hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto's bleeding score, and perioperative hemostatic protocols were collected. Results: Among the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). Conclusions: The current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.
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INTRODUCTION: We aimed to evaluate the performance of the fully automated multiparameter CN-6000 hemostasis analyzer. METHODS: Performance evaluation of the CN-6000 analyzer was conducted for 10 tests including prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen level, anti-Xa activity, and antithrombin activity using a unique portfolio of liquid ready-to-use reagents. Precision, sample and reagent carryovers, throughput, and sample turnaround time (STAT) function were prospectively assessed. Results from 343 samples (normal subjects, critically ill patients, patients receiving anticoagulants, subjects with high or low fibrinogen levels, and patients with decreased levels of factor II, V, VII, and X) were compared to those obtained on the STA-R Max 2® analyzer using dedicated reagents. RESULTS: Total precision (coefficient of variation) was below 7% for all parameters in both normal and pathological ranges. For all analyzed parameters, results obtained on the CN-6000 were strongly correlated with those obtained on the STA-R Max 2®analyzer. Agreement between both instruments was excellent for all assays. The CN-6000 demonstrated a 30% higher throughput compared to the STA-R Max 2® (258 vs 185 tests per hour for a panel of tests including PT, aPTT, fibrinogen, factor V, anti-Xa, and D-Dimer). STAT turnaround time for critical care samples testing was <7 minutes. CONCLUSIONS: The CN-6000 analyzer performs equivalently or better than the STA-R Max 2® with a significantly improved throughput. This new hemostasis multiparameter analyzer appears to be particularly well suited for coagulation laboratories which require high sample throughput and manage high numbers of nonstandard and critical care samples.
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Hemostasia , Laboratórios , Testes de Coagulação Sanguínea/métodos , Humanos , Tempo de Tromboplastina Parcial , Tempo de ProtrombinaRESUMO
Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35-56) years, with a median body mass index of 30 (27-35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8-16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin-antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p < 0.01) and fibrin formation markers (fibrin monomers, p < 0.001) significantly increased, further resulting in significant decreases in platelet count (p < 0.0001) and fibrinogen level (p < 0.001). PAI-1 levels significantly decreased from baseline to day 7 (p < 0.0001) in all ARDS patients. These changes were more marked in COVID-19 patients, resulting in 14 nonfatal and 3 fatal bleeding. Additional studies are warranted to determine whether monitoring of thrombin generation and fibrinolysis markers might help to early predict bleeding complications in COVID-19 patients supported by ECMO.
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Coagulação Sanguínea , COVID-19/terapia , Oxigenação por Membrana Extracorpórea/efeitos adversos , Fibrinólise , Síndrome do Desconforto Respiratório/terapia , Adulto , COVID-19/sangue , COVID-19/complicações , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/complicações , Fator de von Willebrand/análiseRESUMO
Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used in Coronavirus disease-19 (COVID-19) patients with the most severe forms of acute respiratory distress syndrome (ARDS). Its use is associated with a significant hemostatic challenge, especially in COVID- 19 patients who have been demonstrated to otherwise present a COVID-19-associated coagulopathy. The systematic use of unfractionated heparin therapy to prevent circuit thrombosis is warranted during ECMO support. The clinical presentation and management of heparin-induced thrombocytopenia, which is a rare but life-threatening complication of heparin therapy, has not been described in those patients yet. We report herein two cases of laboratory-confirmed HIT in COVID-19 patients with severe ARDS admitted to our intensive care unit for VV-ECMO support and the successful use of argatroban as an alternative therapy. We also provide a brief literature review of best evidence for managing such patients. The diagnosis and management of HIT is particularly challenging in COVID-19 patients receiving ECMO support. An increased awareness is warranted in those patients who already present a procoagulant state leading to higher rates of thrombotic events which can confuse the issues. Argatroban seems to be an appropriate and safe therapeutic option in COVID-19 patients with HIT while on VV-ECMO.
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Anticoagulantes/efeitos adversos , COVID-19/terapia , Oxigenação por Membrana Extracorpórea , Heparina/efeitos adversos , Síndrome do Desconforto Respiratório/terapia , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , Adulto , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-IdadeAssuntos
Betacoronavirus , Transtornos da Coagulação Sanguínea/sangue , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Síndrome de Resposta Inflamatória Sistêmica/sangue , Adulto , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/epidemiologia , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Fator de von Willebrand/metabolismoRESUMO
BACKGROUND: Percutaneous left atrial appendage closure (LAAC) exposes to the risk of device thrombosis in patients with atrial fibrillation who frequently have a contraindication to full anticoagulation. Thereby, dual antiplatelet therapy (DAPT) is usually preferred. No randomized study has evaluated nonvitamin K antagonist oral anticoagulant after LAAC, and we decided to evaluate the efficacy and safety of reduced doses of rivaroxaban after LAAC. METHODS: ADRIFT (Assessment of Dual Antiplatelet Therapy Versus Rivaroxaban in Atrial Fibrillation Patients Treated With Left Atrial Appendage Closure) is a multicenter, phase IIb study, which randomized 105 patients after successful LAAC to either rivaroxaban 10 mg (R10, n=37), rivaroxaban 15 mg (R15, n=35), or DAPT with aspirin 75 mg and clopidogrel 75 mg (n=33). The primary end point was thrombin generation (prothrombin fragments 1+2) measured 2 to 4 hours after drug intake, 10 days after treatment initiation. Thrombin-antithrombin complex, D-dimers, rivaroxaban concentrations were also measured at 10 days and 3 months. Clinical end points were evaluated at 3-month follow-up. RESULTS: The primary end point was reduced with R10 (179 pmol/L [interquartile range (IQR), 129-273], P<0.0001) and R15 (163 pmol/L [IQR, 112-231], P<0.0001) as compared with DAPT (322 pmol/L [IQR, 218-528]). We observed no significant reduction of the primary end point between R10 and R15 while rivaroxaban concentrations increased significantly from 184 ng/mL (IQR, 127-290) with R10 to 274 ng/mL (IQR, 192-377) with R15, P<0.0001. Thrombin-antithrombin complex and D-dimers were numerically lower with both rivaroxaban doses than with DAPT. These findings were all confirmed at 3 months. The clinical end points were not different between groups. A device thrombosis was noted in 2 patients assigned to DAPT. CONCLUSIONS: Thrombin generation measured after LAAC was lower in patients treated by reduced rivaroxaban doses than DAPT, supporting an alternative to the antithrombotic regimens currently used after LAAC and deserves further evaluation in larger studies. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03273322.
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Apêndice Atrial/fisiopatologia , Fibrilação Atrial/terapia , Função do Átrio Esquerdo , Cateterismo Cardíaco , Terapia Antiplaquetária Dupla , Inibidores do Fator Xa/administração & dosagem , Fibrinolíticos/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Rivaroxabana/administração & dosagem , Trombose/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antitrombina III , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Cateterismo Cardíaco/efeitos adversos , Terapia Antiplaquetária Dupla/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinolíticos/efeitos adversos , França , Frequência Cardíaca , Humanos , Masculino , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Projetos Piloto , Inibidores da Agregação Plaquetária/efeitos adversos , Protrombina , Rivaroxabana/efeitos adversos , Trombose/sangue , Trombose/diagnóstico , Trombose/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
: We report herein the successful perioperative management of a 57-year-old man with a type I Glanzmann thrombasthenia undergoing coronary artery bypass graft surgery and right carotid endarterectomy. The patient suffered from several lesions in the three major coronary arteries and in the right carotid necessitating surgery. Prophylactic human leukocyte antigen (HLA)-matched platelets transfusions were continuous administrated before, and through the immediate perioperative period. Posttransfusion platelet recovery was monitored using flow cytometry to determine the percentage of circulating platelet expressing CD61 (ß3). No bleeding complications occurred during and following the procedure. The patient did not develop HLA antibodies or αIIbß3 antibodies. Thrombophilia screening revealed a heterozygous G20210A prothrombin gene mutation. The patient also suffered from an atrial fibrillation, necessitating anticoagulation therapy. During the hospital stay, a treatment with vitamin K antagonists for stroke prevention was initiated. The patient was discharged 8 days following surgery, and no further complications occurred during the 6 months follow-up.
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Artérias Carótidas/cirurgia , Ponte de Artéria Coronária , Vasos Coronários/cirurgia , Período Perioperatório , Trombastenia/terapia , Fibrilação Atrial/tratamento farmacológico , Antígenos HLA/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Transfusão de Plaquetas , Acidente Vascular Cerebral/prevenção & controle , Trombofilia/genética , Resultado do TratamentoRESUMO
CONTEXT: Anti-DFS70 antibodies are the most frequent antinuclear antibodies (ANA) found in healthy individuals. We assessed the clinical significance of the presence of anti-DFS70 antibodies. METHODS: We defined a group of patients (n = 421) with anti-DFS70 antibodies and a group of patients (n = 63) with a history of idiopathic arterial and/or venous thrombotic disease and/or obstetric complication (i.e. ≥ 3 miscarriages, fetal death or premature birth with eclampsia). Anti-DFS70 antibodies prevalence was also assessed in a cohort of 300 healthy blood donors. RESULTS: The prevalence of thrombotic disease and/or obstetric complication in the 421 patients with anti-DFS70 antibodies was 13.1% (n = 55) and the prevalence of connective tissue disease was 19% (n = 80). Among the 63 patients with a history of thrombosis and/or obstetric complications, 7 (11.1%) had anti-DFS70 antibodies and among the latter, 5 had no common thrombophilic factor. In contrast, the prevalence of anti-DFS70 antibodies was of 3.0% (9 out of 300) in healthy donors. Finally, the Activated Partial Thromboplastin Time (aPTT) ratio of patients with a history of thrombosis and anti-DFS70 antibodies was lower than the aPTT ratio of other patients, suggesting that thrombotic patients with anti-DFS70 antibodies may have a hypercoagulable state. CONCLUSION: We described here for the first time an immune procoagulant state involving anti-DFS70 antibodies.
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Proteínas Adaptadoras de Transdução de Sinal/imunologia , Autoanticorpos/sangue , Trombofilia/patologia , Fatores de Transcrição/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Estudos de Coortes , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/patologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Prevalência , Trombofilia/epidemiologia , Trombose/patologia , Adulto JovemRESUMO
The Sysmex® CS-5100 is a fully automated multiparameter hemostasis analyzer equipped with a photo-optical clot detection unit, a cap-piercing system and a pre-analytical check screens for interfering substances such as bilirubin, lipids and haemolysis (HIL system). It is designed to perform coagulation tests as well as coagulometric, chromogenic and immunologic assays. The aim of the present study was to evaluate its performance. The intra-assay and inter-assay coefficients of variation (CV) were below 6% for most parameters both in the normal and in the pathological range (exceptions: intra-assay for severe factor VIII deficiency (CV = 7.4%) and for vWFRco (CV = 7.3% and 7.7%); and inter-assay for anti-Xa activity (CV = 8.8%) and vWFRco (9.3% and 11.1%). The measured lower limits of linearity for factor VIII and factor V were satisfactory. No sample or reagent carryover was detected in the conditions of the study. Our results demonstrated that using the Sysmex® CS-5100 analyzer, routine coagulation testing can be performed with satisfactory precision. This automate has the advantage of being connectable to an automation chain.
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Testes de Coagulação Sanguínea/instrumentação , Desenho de Equipamento , HumanosRESUMO
The Sysmex(®) CS-2100i is a fully automated multiparameter hemostasis analyzer equipped with a photo-optical clot detection unit, a cap-piercing system and a pre-analytical check screens for interfering substances such as bilirubin, lipids and haemolysis (HIL system). It is designed to perform coagulation tests as well as chromogenic and immunologic assays. The aim of the present study was to evaluate its performance. The tests performed were routine coagulation (prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII and factor V), chromogenic (antithrombin) and immunologic assays (D-Dimer). The intra-assay and inter-assay coefficients of variation (CV) were below 5% for most parameters both in the normal and in the pathological range (exceptions: intra-assay CV = 5.65% for the fibrinogen in the low range of concentrations; and inter-assay CV = 6% for clotting factor). The measured lower limits of linearity for factor VIII and factor V were satisfactory. No sample or reagent carryover was detected in the conditions of the study. Our results demonstrated that using the CS-2100i analyzer, routine coagulation testing can be performed with satisfactory precision.
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Automação Laboratorial , Hematologia/métodos , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Antitrombina III/análise , Fatores de Coagulação Sanguínea/análise , Testes de Coagulação Sanguínea/instrumentação , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/normas , Testes Diagnósticos de Rotina/instrumentação , Testes Diagnósticos de Rotina/métodos , Contaminação de Equipamentos/estatística & dados numéricos , Fator VIII/análise , Fibrinogênio/análise , Hematologia/instrumentação , Ensaios de Triagem em Larga Escala/normas , Humanos , Kit de Reagentes para Diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores de TempoAssuntos
Anticorpos Monoclonais/efeitos adversos , Paraproteinemias/complicações , Paraproteinemias/terapia , Doenças de von Willebrand/etiologia , Doenças de von Willebrand/terapia , Idoso , Anticorpos Monoclonais Murinos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Paraproteinemias/sangue , Rituximab , Falha de Tratamento , Doenças de von Willebrand/sangueRESUMO
The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.